In conclusion, the present study indicates for the first time that Zonisamide may ameliorate the cognitive impairment through increasing the PSD95 and CREB in T2DM mice, decrease the Aβ load, and rescue the Tau hyperphosphorylation at Ser 396/404 through inhibiting the activity of JNK. This evidence concerns the gene MAPK8 and type 2 diabetes mellitus.